tbuckley/cabot-search huggingface dataset:
Abstract 3726: Histone acetylation axis in the control of RNA Pol2 clusters
Authors: Berkley E. Gryder, Diana Chin, Hyunmin Kim, Issra Osman
Journal: Cancer Research (2023)

Abstract Core regulatory transcription factors (CR TFs) orchestrate the placement of super enhancers (SEs) to activate transcription of cell-identity specifying gene networks and are critical in promoting cancer. We defined the core regulatory circuitry of fusion positive rhabdomyosarcoma (FP-RMS, a cancer of childhood) in primary tumors and cell lines, which includes PAX3-FOXO1 (P3F), MYOD1, SOX8, MYCN and others. To find chemical probes able to selectively inhibit CR TF transcription, we screened the Structural Genomics Consortium epigenetic probe set by RNA-seq. We found that chemical probes along the acetylation-axis, and not the methylation-axis, are able to cause selective disruption of CR TF transcription. Inhibitors of HDACs (acetylation erasers), BRD4 (acetylation readers) and CBP/p300 (acetylation writers) were all able to selectively halt CR TF transcription. For HDACs, this raised a conundrum: why would too much histone acetylation, an active chromatin mark, stop transcription at CR TFs? ChIP-seq showed that CR TFs build SEs that have the largest quantities of histone acetylation and the enzymes that write acetylation (i.e., p300), yet paradoxically also harbor the highest amounts of the opposing histone deacetylases (HDACs). To investigate the architectural effects of disabling HDACs and causing hyper acetylation, we developed Absolute Quantification of Architecture (AQuA) HiChIP, revealing erosion of native SE contacts at CR TFs, and extensive aberrant contacts. This did not cause an elongation defect, but rather removed RNA Pol2 from core regulatory genetic elements and eliminated RNA-Pol2 phase condensates in 20 minutes. We further dissected the contribution of HDAC isoforms using a set of HDAC selective inhibitors, finding HDAC1/2/3 are co-essential to CR transcription. Using HAT inhibitors/degraders, we discovered a profound dependence on CBP/p300 for clustering of Pol2 loops that connect P3F to its target genes. In the absence of CBP/p300, Pol2 long range enhancer loops collapse, Pol2 accumulates in CpG islands and fails to exit the gene body. These results reveal a potential novel axis for therapeutic interference with P3F in FP-RMS and clarify the molecular relationship of P3F and CBP/p300 in sustaining active Pol2 clusters essential for oncogenic transcription. Overall, our data reveals a SE-specific need for balancing histone acetylation states to maintain SE architecture, Pol2 clustering in 3D, and CR TF transcription. Citation Format: Berkley E. Gryder, Diana Chin, Hyunmin Kim, Issra Osman. Histone acetylation axis in the control of RNA Pol2 clusters. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3726.
Abstract 4804: p38 MAPK-dependent regulation of HIF-1 and expression of the hypoxia-inducible gene <i>IGFBP-3</i> in leiomyosarcoma cells
Authors: Nuha Haque, Eric Shelden
Journal: Cancer Research (2023)

Abstract Hypoxia is a common feature of tumor microenvironments and stimulates a variety of responses in a cell. Tumor hypoxia is also associated with poor prognosis in soft tissue sarcomas (STS), including leiomyosarcomas. Genes upregulated under hypoxia contribute to the adaptation of tumor cells and promote tumor progression. Using transcriptome-wide gene expression analysis, we identified IGFBP-3 as one of the most highly upregulated genes in SK-LMS-1 leiomyosarcoma cells in hypoxic conditions. IGFBP-3 has been studied in several tumor types, including STS, and is associated with their altered pathogenesis. Mechanisms responsible for the hypoxia-induced expression of IGFBP-3 in STS have not been previously well defined. Hypoxia results in the stabilization of the hypoxia-inducible transcription factor, HIF-1, and production of reactive oxygen species (ROS) in other cell types. Here, we examined HIF-1 and ROS-dependent mechanisms to determine their roles in the hypoxia-induced expression of IGFBP-3 and other genes in SK-LMS-1 cells. Our data indicate that both ROS production and HIF-1 activation are required for the enhanced IGFBP-3 mRNA expression in hypoxic SK-LMS-1 cells. We also tested the roles of the stress activated protein kinase p38 and the tumor suppressor p53 for their potential to contribute to the regulation of IGFBP-3 expression in these cells. Inhibition of p53 tumor suppressor activity only partially reduced IGFBP-3 expression. We also determined that neither hypoxia nor inhibition of p53 affected the expression of the p53 target gene, CDKN1A (p21), in these cells. In contrast, inhibition of p38 MAPK completely prevented the hypoxia-induced increase in IGFBP-3 expression. Additionally, we found that p38 MAPK inhibition reduced HIF-1 protein accumulation and activity but had no effect on its mRNA expression under hypoxic conditions. Together these results suggest that ROS-dependent activation of p38 MAPK stabilizes HIF-1 and promotes the downstream expression of IGFBP-3. In contrast, p53 appears to have a limited effect on the expression of IGFBP-3 in SK-LMS-1 cells. Our results clarify the signaling pathway involved in the response of soft tissue sarcoma cells to hypoxia and may provide new avenues for intervention in cancer progression. Citation Format: Nuha Haque, Eric Shelden. p38 MAPK-dependent regulation of HIF-1 and expression of the hypoxia-inducible gene IGFBP-3 in leiomyosarcoma cells. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4804.
Abstract 4790: Oxidation in the nucleotide pool as a novel targetable vulnerability in pancreatic ductal adenocarcinoma
Authors: Beatriz Mateo-Victoriano, Ling Zhang, Govindi J. Samaranayake, Cassie Due, Clara Troccoli, Julia Zaias, Nagaraj Nagathihalli, Michael VanSaun, Michael G. Mohsen, Eric T. Kool, Priyamvada Rai
Journal: Cancer Research (2023)

Abstract Oncogenic RAS signaling is mediated by reactive oxygen species (ROS) signaling. However, oncogenic ROS also evoke tumor suppressive damage, necessitating adaptive redox protective mechanisms. We previously reported that MTH1, the main mammalian 8-oxodGTPase, comprises one such critical adaptation. High MTH1 expression significantly correlates with poor disease-free survival in several KRAS-driven tumors. We have shown in RAS-driven xenograft cancer models that MTH1 is critical for the maintenance of ROS-driven signaling and prevention of DNA damage-induced senescence. However, how MTH1 loss affects KRAS-driven spontaneous tumor formation is unknown. We focused on pancreatic ductal adenocarcinoma (PDAC) due to the high prevalence of driving oncogenic KRASG12D mutations, and the lack of MTH1 studies. Therefore, we depleted MTH1 via shRNA in MIA PacCa-2 and SU.86.86 cell lines and generated novel MTH1-null Pdx1Cre; LSL-KrasG12D/+; LSL-Trp53R172H/+ (KPC), Ptf1acre/+;LSL-KrasG12D/+;Tgfbr2flox/flox (PKT) and corresponding MTH1-wildtype strains. We found MTH1 knockdown significantly reduced growth of KRAS-driven PDAC cells, and that germline MTH1 deficiency reduced tumor burden in the short latency PKT but not the long latency KPC animals. The PKT tumors exhibited higher overall 8-oxodGTPase activity and reduced total 8-oxo-dGTPase activity in the MTH1-deficient background, unlike KPC tumors. This finding suggests that in aggressive KRAS-driven tumors, redundant 8-oxodGTPase activity cannot compensate for MTH1 loss to prevent oncogenic stress-induced tumor suppression. Additionally, both MTH1-depleted PDAC cell lines and the smaller MTH1-null PKT tumors had decreased EGFR expression, suggesting MTH1 loss compromises this ROS-driven pathway. RNA-seq analysis revealed MTH1 deficiency altered MDSC gene expression in the PKT model, suggesting better anti-tumor response through improved immune infiltration in a typically immunologically cold tumor. Our results indicate MTH1 targeting could benefit aggressive PDAC stages. We further show PDAC tumors possess redundancy in MTH1 8-oxodGTPase function, which needs to be better understood in order to therapeutically leverage current MTH1 inhibitors, which do not target this redundancy. Citation Format: Beatriz Mateo-Victoriano, Ling Zhang, Govindi J. Samaranayake, Cassie Due, Clara Troccoli, Julia Zaias, Nagaraj Nagathihalli, Michael VanSaun, Michael G. Mohsen, Eric T. Kool, Priyamvada Rai. Oxidation in the nucleotide pool as a novel targetable vulnerability in pancreatic ductal adenocarcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4790.
Abstract 4789: Spin oscillating magnetic field sOMF of oncomagnetic device selectively kills glioma cancer cells by inducing oxidative stress and DNA damage
Authors: Shashank Hambarde, Arvind Pandey, David S. Baskin, Santosh A. Helekar
Journal: Cancer Research (2023)

Abstract A new noninvasive therapeutic device developed in our laboratory called the Oncomagnetic device provides a novel approach to glioblastoma (GBM) treatment. It involves repeated stimulation with oscillating magnetic fields (sOMF) produced by spinning permanent magnets. It is technologically and mechanistically distinct from the Optune® device approved by the FDA for the treatment of newly diagnosed and recurrent GBM. Use of this device in end-stage GBM patients reversed the progression of their recurrent tumor causing &amp;gt;30% reduction in its contrast-enhanced volume within 4-6 weeks of treatment. Mice with implanted mouse glioma cells in their brains also showed marked reduction in tumor size, increased survival (p&amp;lt; 0.05, n = 10) and higher DNA damage (γ-H2AX foci) after sOMF treatment with a whole-body stimulation method developed by us. Normal mice exposed to sOMF for 4 months had no adverse effects on the brain and other organs. In-vitro, sOMF markedly increased reactive oxygen species (ROS) levels in cancer cells leading to the selective death of these cells, while sparing normal neurons and astrocytes. Detection of γ-H2AX and 53BP1 foci showed that sOMF caused significant DNA damage in GBM cells and diffuse intrinsic pontine glioma (DIPG) cells but not in normal astroglial SVGp12 cells. Furthermore, sOMF exposure for just 2 h resulted in &amp;gt;40% loss of surviving GBM and DIPG cell colonies detected by clonogenic cell survival assay, similar to that produced by 2 Gy radiation dose. This loss was rescued by the antioxidant Trolox. These results indicate that sOMF stimulation has high anticancer potency comparable to low dose radiation therapy at the cellular level with an underlying mechanism of action that is substantially different from that proposed for Optune® TTF. Citation Format: Shashank Hambarde, Arvind Pandey, David S. Baskin, Santosh A. Helekar. Spin oscillating magnetic field sOMF of oncomagnetic device selectively kills glioma cancer cells by inducing oxidative stress and DNA damage. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4789.
Abstract 5413: AIVE, an artificial intelligence protein miner based on omics data to discover new cancer druggable candidates
Authors: Dongwan Hong
Journal: Cancer Research (2023)

Abstract Recently, AI software including Alphafold, RoseTTAFold and ESMFold, can predict protein structures based on amino acid sequences, and DeepMind (Alphafold2) and Meta (ESMFold) opened hundreds of millions of protein structures to world-wide clinical researchers. These tools are possible to generate protein structures in a shorter time and less cost than traditional protein study methods. Finally, they can lead to the advent of the protein rush generation. To evaluate accurately and quickly the prediction of structures of mutations embedding in protein sequences, we developed an Artificial Intelligence analytics toolkit for predicting Virus mutation in protEin (AIVE; http://ai-ve.org) that clinical researchers can use easily on web. An amino acid property eigen selection score (APESS) defined in AIVE is a comprehensive mathematical analysis model, andit was calculated basically by below: 1 artificial intelligence base clustering (AIBC) using predicted aligned error (PAE) and per-residue confidence (pLDDT) values, 2 base level change rate (BLCR)using the probability of occurrence of mutation in each amino acid sequence or nucleotide sequence, 3chemical property eigen score (CPES) using amino acid properties (PH, Residue and Hydrophobic),and 4polarity based feature selection (PBFS) using continuous position of polar amino acids including S, C, N, Q, T, and Y [APESS = AIBC ´ BLCR ´ CPES ´ PBFS]. AIVE also calculated the docking score using AlphaFold to estimate protein to protein interaction (PPI) among hosts (or mutations) and provided a graph as final report showing APESS distribution among mutation group, and evaluation of APESS and docking score. For example, according to APESS score in lung cancer, we can find out the feasibility of structure transformation of H-bond in EGFR protein (L858R) tyrosine kinase and also show the differences of tyrosine kinase affinity between each lung cancer patients. However, for the T790M mutation of EGFR protein, there was no significant difference compared with the wild type (790). The execution time of AIVE (GPU based web server platform) depends on the length of the input sequence, and it completes such an example case in an average of 2-3 hours. AIVE can suggest anti-cancer candidates in protein-level and present a precision medicine model which is available to implement close to real time. Citation Format: Dongwan Hong. AIVE, an artificial intelligence protein miner based on omics data to discover new cancer druggable candidates. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5413.
Abstract 4782: A biflavonoid TY1 induced mitochondrial oxidative stress in 5-fluorouracil-resistant colorectal cancer cells to suppress tumor progression
Authors: Ting-Yan Jian, Shian-Ying Sung, Yu-Ling Lin
Journal: Cancer Research (2023)

Abstract The high metastasis and drug resistance of colorectal cancer (CRC) cause high mortality and rank third among the top ten cancer deaths. TY1 is a biflavonoid isolated from Taxus x media cv. Hicksii. We have previously reported that TY1 inhibits metastatic behavior by inhibiting F-actin polymerization. However, the biological activities of TY1 to overcome drug resistance remain unclear. In this study, we investigated the pharmacological mechanism of TY1 for inhibiting 5-fluorouracil (5-FU)-resistant CRC cells and its therapeutic effect. The 5-FU sensitive (COLO205) and 5-FU resistant (HT-29) CRC cells were used to determine the antitumor activity of TY1. Bioinformatic analysis was conducted to explore the antitumor effects of TY1 in 5-FU resistant HT-29 cells. The effects of TY1 on 5-FU-resistant CRC cells were determined by cell-based analyses, including MTT assay, cellular and mitochondrial ROS-superoxide detection, and confocal images. Finally, the therapeutic effects of TY1 were evaluated in HT-29 xenograft CRC mice. We found TY1 inhibited cell proliferation but did not affect the cell cycle. TEM images showed that TY1 induced vacuole production. Transcriptome data indicated that interferon-related genes specifically mitochondrial interferon alpha-inducible protein (IFIP) were significantly decreased after TY1 treatment. TY1 increased oxidative stress generated by reactive oxygen species (ROS) and superoxide. When IFIP was overexpressed, TY1-induced oxidative stress was reduced. In xenograft CRC mouse, TY1 effectively inhibited tumor growth. The anticancer activity of TY1 is attributed to TY1-induced ROS and superoxide by downregulating mitochondrial IFIP expression. Therefore, these data suggest that TY1 may be a promising new compound in the treatment of 5-FU-resistant CRC. Citation Format: Ting-Yan Jian, Shian-Ying Sung, Yu-Ling Lin. A biflavonoid TY1 induced mitochondrial oxidative stress in 5-fluorouracil-resistant colorectal cancer cells to suppress tumor progression. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4782.
Abstract 4809: A novel microfluidic platform for PDAC organoid culture and drug screening
Authors: Marlene Geyer, Daniel Schreyer, Lisa-Marie Gaul, Désiréé Goubert, Susanne Pfeffer, Christian Pilarsky, Karla S. Queiroz
Journal: Cancer Research (2023)

Abstract Pancreatic Ductal Adenocarcinoma (PDAC), the most common pancreatic cancer type, will become the second leading cause of cancer-related deaths by 2030 with mortality rates of up to 93%. Current standard-of-care for patients with PDAC includes chemotherapeutic regimens and pancreatic cancer surgery. However, only 20% of the patients are eligible for surgery due to late diagnosis. Although chemotherapeutic regimens are the leading treatment to PDAC patients, these are still very limited and the development of resistance to treatment is often observed. PDAC tumors are characterized by high-density stroma and hypovascularization, therefore these present high interstitial pressure and hypoxia. These features potentially interfere with the efficiency of chemotherapeutic drugs and highlight the urgent need for novel PDAC screening platforms. Here, we describe the establishment of PDAC organoid cultures in the MIMETAS OrganoPlate®. The aim of this project was to determine the treatment response of PDAC organoids in mono-, and co-culture with pancreatic stellate cells (PSCs) under hypoxic and normoxic conditions. To recapitulate in-vivo like conditions, the 2-lane OrganoPlate® from MIMETAS was used to study organoid growth and sensitivity to treatment. Several standard of care (chemo-)therapeutics were tested on PDAC organoids embedded within an extracellular matrix in the Organoplate® 2-lane. These were exposed to chemotherapeutic treatments for 72h. PDAC organoids showed an overall better survival when grown in co-culture with PSCs. Interestingly, organoids grown in co-culture showed a higher survival rate under hypoxic conditions. In contrast, when grown in monoculture cell viability was higher or similar under normoxic conditions than in hypoxia for the different chemotherapeutics. The OrganoPlate® 2-lane provides an excellent platform for (co-) cultivation and high-throughput phenotypic drug screening of PDAC organoids, thereby potentially enabling the development of novel in-vivo like model systems for efficient patient stratification and drug discovery. Citation Format: Marlene Geyer, Daniel Schreyer, Lisa-Marie Gaul, Désiréé Goubert, Susanne Pfeffer, Christian Pilarsky, Karla S. Queiroz. A novel microfluidic platform for PDAC organoid culture and drug screening. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4809.
Abstract 1020: Tissue-informed ctDNA MRD assay detects post-surgery minimal residual disease in HCC patients
Authors: Jie Hu, Haoran Tang, Feng Xie, Yue Zhang, Shidong Jia, Jian Zhou
Journal: Cancer Research (2023)

Abstract Introduction: Residual disease detection is a significant clinical need in post-surgery treatment of resectable hepatocellular carcinoma (HCC) patients. Previous NGS-based studies targeting fixed genomic regions had reported that circulating tumor DNA (ctDNA) could provide evidence for prognosis prediction during HCC treatment. However, the sensitivity of methods was limited and could not reach the threshold of minimal residual disease (MRD) test. Here we reported a baseline tissue -informed ctDNA NGS assay, detecting MRD in HCC patients who received hepatectomy and predicted prognosis in MRD positive patients. Methods: The study retrospectively enrolled 200 early-stage HCC patients who received surgical resections. Tumor and normal tissue samples were collected respectively through surgery. Plasma samples were collected 7 days or more post-surgery. In the completed pilot study, samples from 17 patients were tested by a baseline tissue-informed MRD assay (PredicineBEACON). Tumor-specific mutations were identified by whole exon sequencing on baseline tumor and normal tissue samples. For each patient, up to 50 mutations were selected through bioinformatics pipelines for personalized MRD panel design, in combination with a fixed panel of 500 tumor actionable hotspots. The post-surgery plasma samples were then tested for MRD with the panel through ultra-deep sequencing(100,000X). Afterward, genomic tumor fraction proportions were calculated. Results: In the completed pilot study, 12 of 17 patients (70.6%) were called MRD positive based on tests of post-surgery plasma. Among MRD positive patients, 3 were identified as MRD risk high (proportion of tumor fraction≥0.1%) and MRD risk of others were moderate (proportion of tumor fraction&amp;lt;0.1%). The tumor fraction proportion of MRD positive patients varied from 0.013% to 17.84% (median 0.042%). The recurrence free survival (RFS) and overall survival (OS) probabilities were significantly correlated with MRD risk: the median RFS of two groups(risk-high vs. risk-moderate) was 10.1 months vs. 57.4 months (p-value&amp;lt;0.001), while the median OS of two groups (risk-high vs. risk-moderate) was 31.2 months vs. 57.4 months(p-value=0.028). Conclusions: Baseline-informed ctDNA NGS assay showed ultra-sensitive capability of MRD detection on early-stage HCC patients, with outstanding positive rate through plasma samples collected 7 days post-surgery. The MRD risk provided significant prognostic evidence for patient survival and disease relapse. Citation Format: Jie Hu, Haoran Tang, Feng Xie, Yue Zhang, Shidong Jia, Jian Zhou. Tissue-informed ctDNA MRD assay detects post-surgery minimal residual disease in HCC patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1020.